NK cell immunotherapy to reduce relapse after haploidentical transplant for high-risk pediatric AML
Todd Fehniger
MD PhDWashington University in St. Louis
Project Term: July 1, 2023 - June 30, 2026
Leukemia recurrence remains the most common type of treatment failure after allogeneic hematopoietic cell transplant for children and young adults with high-risk acute myelogenous leukemia (AML), occurring in 40-50% of patients. Novel treatment strategies are needed to attain durable remissions and provide long-term cure. We have developed a novel memory-like (ML) NK cell immunotherapy that has demonstrated potent activity against AML in preclinical and early clinical studies. We propose a new clinical trial combining donor-derived ML NK cells adoptive cellular therapy with modified αβT cell-depleted haploidentical HCT to enhance graft-versus-leukemia and reduce relapse in pediatric and young adult patients with high-risk AML.
High-risk acute myeloid leukemia (AML) in children and young adults remains a significant clinical challenge. Current therapy includes multi-agent chemotherapy followed by stem cell transplant. Despite this aggressive approach, 40% of patients relapse. Treatment options for children with AML that has relapsed after stem cell transplant are limited and the chance of cure is exceedingly low. Relapsed AML accounts for more than 50% of all childhood leukemia-related deaths. New therapies with enhanced anti-leukemia activity that reduce risk of relapse are desperately needed for children with high-risk AML. We propose to apply a new form of immunotherapy discovered at Washington University to augment stem cell transplant for treatment of high-risk AML. This therapy includes collecting a donor’s natural killer (NK) cells and activating them to potently respond to the patient’s leukemia cells. We have previously shown that these activated, memory-like (ML) NK cells have significantly enhanced anti-leukemia functionality. In previous clinical trials, we have utilized ML NK cells in both adult and pediatric patients with relapsed AML. ML NK cells were safe without significant toxicities and were effective, inducing remission in over half of these heavily pretreated patients with aggressive AML. The overall goal of our project is to advance this new NK cell-based immunotherapy to improve survival of children with AML. In this proposal, we will implement these novel ML NK cells earlier in therapy with the objective of preventing disease relapse in children and young adults with high-risk AML. We will complete a clinical trial combining donor ML NK cells with a modified stem cell transplant. This treatment approach will establish a unique immune environment for enhancing ML NK cell activity against residual AML. Additional studies will investigate the function of the activated donor NK cells in killing AML cells within patients treated on the clinical trial. This study will establish the safety, feasibility and efficacy of a ML NK cells in combination with stem cell transplant that will provide the foundation for a larger multi-center clinical trial. This novel NK cell immunotherapy approach has the potential to establish sustained remission and cure in high-risk pediatric AML patients.